DIABETES MELLITUS

Heterogeneous group of disorders with hyperglycaemia

A state of chronic hyperglycaemia caused by a defect in insulin secretion, action or both that results in various metabolic disturbances.

Clinical Features

Glycosuria

Microangiopathy

Fasting hyperglycaemia

Neuropathy

Vascular Disease

Classification

Type 2

Type 1

Secondary

Inherited

Therefore no insulin is produced & secreted

Pancreatic B cells destroyed/inflammed by anti-islet cells antibodies. The antibodies are produced in response to trigger usually viral infecions

Insulin dependent

Affects ppl under 20

Presentation is acute

Patients usually lean

DKA

Drugs

Pregnancy

Major illness

Insulin receptor and postreceptor defects

Trauma

Abnormal beta cell secretion

Obesity

Circulating insulin antagonists

Oral contraceptive

Thiazide diuretics

Gradual

Insulin resistance

Islets normal

Hyperosmolar non-kinetic coma (HONK) common

Affects over 40s

Severe hyperglycaemia causing dehydration w/o ketoacidosis

Occurs in elderly diabetics with adequate insulin to prevent ketoacidosis but inadequate to prevent gluconeogenesis

As a result, liver makes glucose which the increases serum osmolarity

Complication secondary to dehydration

This leads to decreased tissue perfusion with lactic acidosis,renal shutdown & cerebral thrombosis

Tx same as DKA

Hyperviscosity

Thromboembolism increased due to hyperosmolarity therefore anticoagulants are needed.

Strong genetic component worsened by obesity

Drugs

Gestational DM

Major damage to pancreas (90% destroyed) due to:

Endrociopathies

Acromegaly

Hyperthyroidism

Cushings Syndrome

Contraceptives

Thiazide diuretics

Corticosteroids

Surgical Resection

Haemochromatosis

Chronic Pancreatitis

Complications

Chronic

Acute

Coma

Hypoglycaemia

Hyperglycaemia with:

HONK

Lactic Acidosis

Ketoacidosis

From insulin overdose

Macrovascular

Neuropathy

Microvascular lesions

Infection predisposition

Mechanism

Sorbitol & Fructose

Activation of Protein Kinase C

Excess Oxygen Free Radicals

Advanced Glycation End Products

Harmful compounds formed when protein covalently combine with sugar in bloodstream.[ glycation]

Autoimmune disease characterizied by pancreatic b cell destruction and an absolute deficiency of insulin.

Caused by combination of peripheral resistance to insulin action and an inadequate secretory response by pancreatic b cells.

Clinical presentation seen when more than 90% beta cells destroyed.

Loss of self tolerance

AGE binds to RAGE(receptor) expressed on inflamm. cells

Sheer stress ( all mentioned cause this)

Hyperglycaemia accelerates process

due to (-) elasticity of CT

Basement membrane of blood vessel:

(-) breakdown

(+) protein deposition

(+) fluid infiltration

(+) LDL trapping

(+) synthesis of matrix

(+) growth factors from mesangium & macrophage

Atheroma

Proinflammatory molecules and cytokines

(+) matrix & BM

Inflammation & cytokines

Angiogenesis

(-) myoinositol

Water into cell

Leads to damage

(+) injury Schwann cells & pericytes

Thickening of basement membrane

Kidney

Pregnancy

EYE

Microaneurysms

Haemorrhages

Diabetic retinopathy

Exudates

All can lead to blindness

Thickening of BM

Pyelonephritis

Kimmelstiel-WIlson lesions

Renal Papillary Necrosis

Nodules of (+) mesangial matrix (glomerulosclerosis)

With altered charge

Leading to proteinuria

And so (+) permeability

Thickened vessel BM

These lead to poor acute inflammatory response to bacteria

(+) sugar in urine

Vessel changes in papillae

Leads to infarction of papillae

Swelling from pyelonephritis

Polyhydramnios

Neontal Distress Syndrome

Large foetus

Pregnancy Induced HPT

(+) congenital malformations

This leads to obstructed labor

Premature contractions & labor

Early membrane rupture

Thus bcoz of lack of surfactant

Lungs immature

Coronary Atheroma

Peripheral Vascular Disease

Atherosclerosis

Early onset bcoz DM accelerates it

More severe for DM

Cerebrovascular Accident

Stroke

Rupture (hemorrhagic) OR obstruction (ischaemic) of BV

Leads to restriction of circulation

Due to acc. of fats & scar tissue

Degen. of bv artery walls

Predisposing to Thrombi formation

BV outside heart & braiin narrow, block or spasms.

(-) blood flow to peripheral tissues

Gangrene of feet & toes

Ischaemic & neuropathic ulceration

superimposed infxn in deep tissues(Cellulitis) & bone (Osteomyelitis)

Diabetic foot

Direct effect of chronic hyperglycaemia causing peripheral neeuropathy

BM thickening with subsequent capillary closure resulting in ischaemic demyelination & axonal degeneration

The excess glucose is stored and deposited as fat causing the fetus to be Macrosomiac

Responds by producing lots of insulin to ensure use of the glucose.

In maternal hyerglycaemia, fetal pancreas senses high glucose

Too much insulin in fetus delays surfactant production

Which can lead to birth injuries

This induces islet cell hyperplasia

Granular capsule

Cut Surface

Hilar fat

Pale cortex

The glucose alter the conformation of glycated proteins and therefore affects their function.

Hyperglycaemia due to glycogenolysis & gluconeogenesis

Keto acidosis due to ketogenesis [ from excess acetly coA( beta oxidation) ] and lactic acidosis( anaerobic metabolism)

Sweet breath [ketogenesis produces acetoacetate which converts to acetone & ends in the blood, diffuses into lungs and is exhaled bcoz its volatile]